Transplantation of organs such as liver, lung, kidney, heart, spleen, cornea, and pancreas has become a relatively routine mode of therapy for patients suffering from end stage organ disease. Despite major achievements in organ transplantation with regard to improved techniques, more specific immunosuppression, and better understanding and treatment of complications, preservation of organs prior to transplant still remains a critical issue.
Organ storage and preservation typically is done under hypothermic conditions in order to inhibit cellular metabolism and thereby suppress the rate of cellular deterioration. It also is important, however, to counteract effects of hypothermia (e.g., cell-swelling, reduced plasma membrane integrity, and enzyme leakage) in order to minimize organ damage. Some preservation solutions include one or more non-permeable components to reduce cell swelling, prevent intracellular acidosis, maintain plasma membrane integrity, and prevent expansion of the intracellular space. Some preservation solutions also contain antioxidants for scavenging oxygen radicals, and adenosine triphosphate (ATP) precursors to provide energy upon reperfusion.
A very commonly used organ preservation solution is the University of Wisconsin (UW) solution, also sold under the trade name VIASPAN™ by DuPont. This solution typically is considered to provide clinically good preservation of kidneys for up to 24 hours, livers for up to 12 hours, and hearts and lungs for about 5 hours of cold ischemic time. The major effective component of UW solution is 100 mM lactobionate, which has an insoluble nature that maintains the colloid oncotic pressure of the solution, delaying or preventing equilibration of the solution across the cell membrane and thus delaying cellular edema.
Several other types of organ preservation solutions also have been used to keep organs alive during transport from donor to recipient. These include EuroCollins (see, Collins et al. (1992) Kidney Int. Suppl. 38:S197-202), Marshall (or Ross-Marshall) solutions, HTK solution (marketed as CUSTODIOL® by Essential Pharmaceuticals, Newtown, Pa.), and CELSIOR®. EuroCollins solution contains high concentrations of potassium (110 mM), phosphate (60 mM), and glucose (180 mM). Ross-Marshall solutions have electrolytic compositions similar to those of EuroCollins solution, except that citrate replaces phosphate and mannitol replaces glucose. The citrate acts as a buffer and chelates with magnesium to form an impermeable molecule that helps stabilize the extracellular environment. Bretschneider HTK solution (see, e.g., U.S. Pat. No. 4,415,556) includes histidine as the buffer, tryptophan as a membrane stabilizer, and ketoglutarate as the energy substrate. CELSIOR® is an extracellular-type, low-viscosity solution that couples the impermeant, inert osmotic carrier from UW solution (using lactobionate and mannitol) and the strong buffer from Bretschneider HTK solution (using histidine).